Laminin-1 promotes neurite outgrowth of both central and peripheral neurons of the rodent (Liesi, 1990). One of the neurite outgrowth domains of laminin-1 has been mapped to the C-terminal decapeptide RDIAEIIKDI (SEQ ID NO: 1) (P1543; p20; Liesi et al., 1989) of the γ1-chain of laminin-1.
Both human brain and spinal cord neurons attach and respond by neurite outgrowth to mouse laminin-1. Sequence analysis of the human brain isoforms of laminin-1 show approximately 96-100% homology to the mouse prototype (Liesi et al., 2001).
In recent years, multiple and diverse functions of laminin-1 have been reported in neural tissues. For example, laminin-1 has been shown to prevent neurotoxicity of the amyloid-β-peptide involved in neuronal death of Alzheimer disease (Bronfman et al., 1996; Drouet et al., 1999). Laminin-1 further affects development of dendritic spines of the cerebellar Purkinje cells (Seil, 1998), and influences memory processing by modulation of LTP (Nakagami et al., 2000). As most of the members of the laminin-superfamily are also present in neurons and glial cells of the human embryonic CNS (Liesi et al., 2001), laminins may have specific and diverse effects on development and mature function of the human CNS.
Using specific γ1 laminin antibodies on cultures of central neurons, the neurite outgrowth domain of the γ1-chain of laminin-1 has been shown to play a major role in neuronal migration and axon guidance. The nuclear rotation phase of cerebellar neuronal migration (Liesi et al., 1995), neuronal differentiation (Matsuzawa et al., 1996a), and axon guidance of rat hippocampal neurons (Matsuzawa et al., 1998) have all been shown to be influenced by the neurite outgrowth domain of the γ1-chain of laminin-1. In previous studies, we have shown that the neurite outgrowth domain of the γ1-chain of laminin-1 accumulates in brains of Alzheimer disease patients (Murtomäki et al., 1992) as well as in the weaver mouse cerebellum (Murtomäki et al., 1995). Therefore we have proposed that an increased accumulation of high concentrations of the neurite outgrowth domain of the γ1-laminin may be toxic to neurons. In line with this hypothesis, antibodies against the neurite outgrowth domain that neutralize the γ1-chain peptides restore both cell survival and neurite outgrowth of the weaver granule neurons (Liesi and Wright, 1996).
WO publication 93/24155 discloses a medical device, useful as a graft in repairing injured nerve tissues, specifically peripheral nerves, the device containing the decapeptide P1543. WO publication 98/43686 discloses fibrin-based, biocompatible materials for, for instance, peripheral nerve regeneration. The materials contain various bioactive peptides, including the above-indicated decapeptide. Furthermore, Hager et al. (1998) showed that the corresponding peptide derived from mouse laminin-1 modulates the electrical activity the neurons of rat neocortex.
WO publication 94/04560, on the other hand, discloses protein factors having Schwann cell mitogenic activity. The peptide sequences disclosed in the application include a sequence comprising the KDI motif. Use of the factors for e.g. neural regeneration is suggested.
U.S. Pat. No. 5,780,090 discloses flavoring ingredients for food products, comprising tripeptides having hydrophobic amino acid residues. Preparation of the tripeptide KDI is described in the patent, but no medical use is suggested for the peptide.
Recently, netrin-1 has been shown to act on central neurons via a G-protein coupled receptor mechanism (Corset et al., 2000). Interestingly, the KDI-sequence is present in the chicken netrin-1 (Serafini et al., 1994), and the human netrin-protein (Meyerhardt et al., 1999) also has this domain, although modified. It is unclear, however, if the presence of this short sequence has any functional significance in these proteins. The KDI-sequence may be hidden in netrins either by conformation or glycosylation of the proteins.